Terpenoids comprise a substantial portion of the small molecule vocabulary of nature, mediating diverse processes ranging from pathogen defense to pollinator attraction, with useful applications as anti-cancer drugs, pesticides, flavorings, and fragrances. The biosynthesis of these products is conducted by terpene cyclase enzymes, which catalyze transformations of acyclic, achiral, isoprenoid subsrates into muticyclic, multichiral products. The enzyme-catalyzed reaction is initiated by ionization of the diphosphate moiety of their C10, C15, or C20 substrates geranyl, farnesyl, or geranylgeranyl diphosphate, respectively. The resulting allylic carbocation is channeled through a series of electrophilic cyclizations and rearrangements, such as alkyl and/or hydride shifts, to produce stereospecific products. Previous structural and functional data will serve as the foundation to guide mutagenesis on the model system 5-epi-Aristolochene synthase and extended to other cyclases to test mechanistic hypotheses. A multifaceted approach combining x-ray crystallography, enzyme kinetics, and analytical chemistry techniques will be applied to analyze the functional consequences of designed structural changes. Elucidation of how terpene cyclases control the regiochemistry of the cyclization reaction they catalyze will provide a fundamental understanding of the structure/function relationship in these enzymes. Ultimately, this knowledge will enable complex organic synthesis of biologicallv important molecules through protein engineering.